The CD4 cell count restored by HAART was evaluated as a prognostic indicator for a new AIDS event or death. Figure 3 shows the person-years at risk, number of AIDS events or deaths, and the event rate according to the most recent CD4 cell count during HAART therapy in 218 patients (15.3% of the total) starting HAART with a CD4 cell count < 50 × 106 cells/l. While there was a relatively high rate of AIDS or death during the time in which the patients’ CD4 cell count remained < 50 × 106 cells/l (0.19/person-year; 95% CI, 0.10–0.33; 13 events in 67 person-years), the rate was very small when the CD4 cell count increased to 50–199 × 106 cells/l (0.05/person-year; 95% CI, 0.02–0.10; 9 events in 175 person-years) and > 200 × 106 cells/l (0.03/person-year; 95% CI, 0.005-0.07; 5 events in 144 person-years) (Fig. 3).
When to start antiretroviral therapy in asymptomatic HIV-infected individuals remains a crucial question [5–12]. Ideally, this question should be studied in a randomized controlled trial as in non-randomized studies the decision to initiate antiretroviral therapy may be influenced by factors such as the patients’ potential adherence to therapy or preferences . Nonetheless, the ICONA study provides some evidence to help clinicians and patients to decide when to initiate therapy. Our data showed that there was a similar rise in CD4 cell count in patients starting HAART at a high CD4 cell count compared with patients starting at a lower level. After 24 months of therapy, patients experienced a very similar CD4 cell count rise irrespective of their level of pre-HAART CD4 cell count (i.e. 180 × 106 cells/l). The immune system has much redundancy and reserve and, consequently, dramatic perturbations seem necessary to place a person at risk of AIDS or death. In the natural history of HIV infection such a risk is low in individuals with a CD4 cell count > 200 × 106 cells/l, or even > 100 × 106 cells/l . There is evidence that this is still true even if this count has been restored by HAART [22,26]. In ICONA, patients who started HAART with CD4 cell count of < 50 × 106 cells/l and had a CD4 cell count rise to > 200 × 106 cells/l had an extremely low risk of subsequent occurrence of an AIDS-defining illness or death [5 events per 144 person-years]. This was also observed in a similar large clinical observational database . The majority of our patients (90.8%) for whom results were available after 96 weeks had achieved > 200 × 106 cells/l by 2 years of therapy irrespective of their pre-HAART CD4 cell count. There was no evidence that starting therapy at > 350 × 106 cells/l instead of at 201–350 × 106 cells/l offered any increased immunological benefit at 2 years after starting HAART.
The rate of virological failure by 96 weeks of therapy was significantly higher in patients starting with a CD4 cell count ≤ 200 × 106 cells/l (Fig. 2) but there was no difference in the Kaplan–Meier estimate of virological failure in patients starting at 201–350 or at > 350 × 106 cells/l (Fig. 2). This was confirmed by a Cox regression analysis, which was also adjusted for pre-HAART viral load levels (Table 2). In our study, pretherapy viral load was not associated with the risk of virological failure (Table 2). This is in conflict with other previous reports [14,27]. However, these other studies were not restricted to antiretroviral-naive patients and their definition of the virological endpoint and the statistical modelling used were different.
There are a number of limitations to this study. In an observational setting, it is possible that patients starting therapy at a low CD4 cell count are intrinsically different from those starting at a higher value. For example, the former might be perceived by medical staff to be less likely to adhere to therapy . Unfortunately, adherence to treatment was assessed (via self-reported questionnaire) only on a subset of enrolled patients and no data are available as yet. Additionally, the quality of life of patients after starting HAART was not assessed. Viral load was assayed using different methods and no attempt was made to standardise these values. Since there is evidence that RT-PCR measurements for a specimen are about twofold higher than those found by the branched DNA assay  this could be source of bias. However, our results were not changed if a correction was applied for this (data not shown). The Cox regression analysis was stratified by centre and these tended to use the same assay for all their samples. Similarly, the ‘time to virological failure’ analysis could be affected by how patients who are lost to follow-up were handled. Again, the conclusions were unchanged when the survival analysis defined patients lost to follow-up as failures.
Our study does not directly address the question of what is the risk of developing an AIDS-defining illness for a patient who decides to delay the initiation of therapy until his/her CD4 cell count has fallen to < 200 × 106 cells/l compared with another patient who decides to start HAART at approximately 350 × 106 cells/l. This is an important point as developing AIDS-defining illnesses is associated with poor quality of life and, for example in lymphomas, with uncertainty regarding the possibility of successfully treatment. Unfortunately, ICONA currently lacks the power for this analysis and it will occur when longer follow-up and a larger number of clinical events are available.
Three recent report meetings addressed the issue of when it would be the optimal time to start HAART in chronic HIV infection [28–30]. One study showed that a higher proportion of patients achieved a viral load ≤ 50 copies/ml if they started HAART at a CD4 cell count ≥ 500 than if they waited until the CD4 count was < 400 × 106 cells/l . A second study showed evidence for more durable undetectable viral load (< 400 copies/ml) in patients started with a CD4 cell count > 350 × 106 cells/l compared with patients starting with < 200 × 106 cells/l; comparison with patients starting at 200–350 × 106 cells/l was not performed . A third study, based on mathematical modelling instead of real data, indicated that immediate initiation of therapy would be recommendable only if this strategy would guarantee a minimum reduction of 15–20% in the rate of virological failure compared with a wide range of strategies implying a delay of therapy . In our study, the difference in the rate of failure at 96 weeks between patients starting at a CD4 cell count of 201–350 and one of > 350 × 106 cells/l was less than 1%.
Although our analysis of an observational clinical database cannot provide categorical answers, it does indicate that patients starting HAART with a CD4 cell count ≤ 200 × 106 cells/l may experience a worse virological response to HAART than those starting with > 350 × 106 cells/l. There is no clear advantage in terms of subsequent virological and immunological response in starting HAART at a CD4 cell count > 350 × 106 cells/l rather than at 201–350 × 106 cells/l. However, further studies are needed to assess whether it is safe to defer HAART until the CD4 cell count reaches 200 × 106 cells/l, as opposed to 350 × 106 cells/l, as currently suggested in the UK HIV treatment guidelines .
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I.CO.N.A. study group in Italy. Ancona: M. Montroni, G. Scalise, A. Costantini, M. S. Del Prete; Aviano (PN): U. Tirelli, G. Nasti; Bari: G. Angarano (scientific committee), L. M. Perulli; Bergamo: F. Suter, C. Arici; Bologna: F. Chiodo (scientific committee), F. M. Gritti, V. Colangeli, C. Fiorini, L. Guerra; Brescia: G. Carosi (scientific committee), G. P. Cadeo, F. Castelli, C. Minardi, D. Vangi; Busto Arsizio: S. Caprioli, G. Migliorino; Cagliari: P. E. Manconi, P. Piano; Catanzaro: T. Ferraro, L. Cosco; Chieti: E. Pizzigallo, F. Ricci; Como: G. M. Vigevani, L. Pusterla; Cremona: G. Carnevale, A. Pan; Cuggiono: P. Viganò, G. C. Ghiselli; Ferrara: F. Ghinelli, L. Sighinolfi; Florence: F. Leoncini, F. Mazzotta, S. Ambu, S. Lo Caputo; Foggia: B. Grisorio, S. Ferrara; Galatina (LE): P. Grima, P. Tundo; Genoa: G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo; Grosseto: M. Toti, Chigiotti; Latina: F. Soscia, L. Tacconi; Lecco: A. Orani, G. Castaldo; Lucca: A. Scasso, A. Vincenti; Mantova: A. Scalzini, F. Alessi; Milan: M. Moroni (study coordinator), A. Lazzarin (scientific committee), A. Cargnel, F. Milazzo, L. Caggese, A. d'Arminio Monforte, V. Testori, F. Delfanti, B. Carini, B. Adriani, S. Garavaglia, C. Moioli; Modena: R. Esposito, C. Mussini; Naples: N. Abrescia, A. Chirianni, O. Perrella, M. Piazza, M. de Marco, V. Montesarchio, E. Manzillo, S. Nappa; Padua: P. Cadrobbi, R. Scaggiante Palermo: A. Colomba, T. Prestileo; Pavia: G. Filice, L. Minoli, F. A. Patruno Savino, R. Maserati; Perugia: S. Pauluzzi, A. Tosti; Piacenza: F. Alberici, M. Sisti; Pisa: F. Menichetti, A. Smorfa; Potenza: C. de Stefano, A. La Gala; Ravenna: T. Zauli, G. Ballardini; Reggio Emilia: L. Bonazzi, M. A. Ursitti; Rimini: R. Ciammarughi, M. Arlotti; Rome: L. Ortona (scientific committee), F. Dianzani (scientific committee), A. Antinori, G. Antonucci, S. D'Elia, G. Ippolito, P. Narciso, N. Petrosillo, G. Rezza, V. Vullo, A. de Luca, A. Del Forno, M. R. Capobianchi, M. Zaccarelli, P. de Longis, M. Ciardi, E. Girardi, G. D'Offizi, F. Palmieri, P. Pezzotti, M. Lichter; Sassari: M. S. Mura, M. Mannazzu; Turin: P. Caramello, A. Sinicco, M. L. Soranzo, D. Giacobbi, M. Sciandra, B. Salassa; Varese: D. Torre; Verbania: A. Poggio, G. Bottari; Venice: E. Raise, S. Pasquinucci; Vicenza: F. de Lalla, G. Tositti; Taranto: F. Resta, A. Chimienti.